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United States Patent O CERTAIN N-(Z-BENZOTHIAZOLYL), AMINOAL-KYLTHIOALKYL CABOXYLIC ACID AlVIIDES AND PROCESS Ernst Habicht,Schaflhausen, Switzerland, assignor to Cilag Limited, Schafihausen,Switzerland, a Swiss com- P y No Drawing. Filed Feb. 27, 1959, Ser. No.795,922

Claims priority, application Switzerland Mar. 13, 1958 11 Claims. (Cl.260-305) The present invention relates to a process for the productionof novel benzothiazoles and their salts.

It was found that benzothiazoles of the general formula wherein Bzrepresents a benzothiazolyl-Z-radical which may optionally besubstituted by a lower alkyl, a lower alkoxy, an alkyl mercapto and/or ahalogen, R and R represent lower straight or branched alkylene radicalsand Am represents a secondary or tertiary amino group, show valuableanaesthetic and particularly antimycotic propertia.

Z-tert. amino 6 dialkylaminoalkoxy benzothiazoles having an antimycoticefiect have already been produced (compare Brit. P. 751,172). The2-dimethylarnino-6- diethylaminoethoxy benzothiazole dihydrochloride (I)thereof has been introduced into the medical practice. A comparativetest of some of the novel compounds obtainable according to the presentinvention and of I has shown them to be approximately equally eflectiveon fungi. The advantage of the novel compounds over I lies in theirbeing likewise very efliective on cocci, such asfor instancestaphlococci, whereas I has no or only a very weak efiect. As in manycases of fungus infection there actually exists a mixed infection(fungus and coccus infection), the advantage of the novel compoundsobtainable according to the present invention is clearly evident.

The novel benzothiazoles defined hereinbefore can be produced byreacting a benzothiazole derivative of the formula with a compound ofthe formula X'-R2--Am III whereby in both formulae Bz, R R and Am havethe aforedefined meaning, whereas one of the symbols X' represents areactive splittable radical, such asfor instance halogen, and the othersymbol X represents the thiol group as such and the tbiol group in formof a salt, respectively.

According to this process, it is for instance possible to react ahalogeno-paratfin-carboxylic acid benzothiazolide, obtainable by usualprocesses, with a secondary or tertiary aminoalkanethiol or with analkali salt thereof. The halogeno-parafiin-carboxylic acidbenzothiazolide can of course also be replaced by an aryl or an alkylsulfonyloxy paraflin-carboxylic acid benzothiazolide.

A preferred method consists in mixing a halogenoparaflin-carboxylic acidbenzothiazolide with a secondary or tertiary aminoalkanethiol in a loweralkyl cyanide, preferably acetonitrile. The reaction is started withoutouter heat input and completed by short heating. Upon cooling, thehydrohalogenide of the resulting aminoalkylmercapto-paraifinoylbenzothiazolide crystallises and can thus be easily isolated.

According to this process, it is likewise possible to proceed in suchmanner as to react a mercapto parafiin-carboxylic acid benzothiazolide,the production of which has been described in British Patent No.699,892, with an aminoalkyl halogenide, working in the presence of basiccondensation agents, such as for instance alkali "alcoholates inalcohols.

As already mentioned, the method of choice is the reaction ofhalogeno-acylamino benzothiazoles with secondary or tertiaryaminoalkanethiols in an aliphatic nitrile, preferably acetonitrile, thisleading directly to the hydro.- halides of the final product.

It is thus for instance possible to react:Z-chloroacetaminobenzothiazole, 2-chloroacetamino-6-methylbenzothiazole, 2-chloroacetarnino-4,6-dimethyl benzothiazole,2-chloroacetamino 6 methoxy benzothiazole, 2-chloroacetamino 6methylmercaptobenzothiazole, 2-chloroacetamino-G-chloroor-6-bromo-benzothiazole, 2-ch1oroacetamino 4,6 dichloro or-4,G-dibromo-benzothiazole, etc. with dimethylaminoethanthiol,diethylaminoethanethiol, di-n-propylaminoethanethiol,di-isopropylarninoethanethiol, di-n-butylaminoethanethiol,pyrrolidinoethanethiol, piperidinoethanethiol, morpholinoethanethiol, aswell as with corresponding propanethiols, such as for instance}3-dimethylarninoethanthiols, 'y -dimethylaminoethanethiols, as alsowith the secondary aminoethanthiols, such as for instanceethylaminoethanthiols, propylaminoethanethiols, butylaminoethanethiols.

It is likewise possible to use in'place of the2-ch1oroacetaminobenzothiazoles the a-halogenopnopionylor the,B-halogenopropionyl compounds.

Valuable benzothiazoles are obtained in the cases where the aryl of thebenzothiazole is substituted by one or two chloroor brorno-atoms, thealkylene radicals R and R together do not contain more than 6 carbonatoms, and Am represents a monoalkylamino group, a dialkylamino group,the pyrrolidino group, the piperidino group and the morpholino group,whereby the monoalkylamino group and the dialkylamino group do notcontain more than 8 carbon atoms.

The resulting benzothiazolides of the Formula I mentioned hereinbeforecan be or are advantageously isolated in form of their salts withinorganic or organic, non-toxic acids. The inorganic acids used for thesalt formation are: sulfuric acid, hydrochloric acid, hydrobromic acid,phosphoric acids; the organic acids are: acetic acid, 'glycolicacid,citric acid, succim'c acid, fum aric acid, maleic acid, dihydromaleicacid, methane-sulfom'c acid, hydroxyethane-sulfonic acid, salicylicacid, undecylenic acid, and other nontoxic acids.

Example 1 20 g. of Z-aminobenzothiazole and 27.3 g. of crystallinesodium acetate are added to 130 cc. of acetone. Subsequently, 18.8 g. ofchloroacetyichloride are added dropwise 35 minutes while cooling andturbinating. The whole is briefly heated to 60 C. and cooled ofi; 50 cc.of hydrochloric acid 1:1 and cc. of water are then added. Theprecipitating crystals are filtered oil with suction and washed withwater. Recrystallisation from glacial acetic acid/Water leads to thepure 2-chloroacetamino benzothiazole, which melts at 158-459" C. Theyield lies between 17 and 18 g. i

A solution of 4.7 g. of dirnethylaminoethanethiol in 10 3 cc. ofacetonitrile is added dropwise while turbinating to 10 g. of the abovechloroacetamino product in 20 cc. of acetonitrile. The temperature risesby itself to 50 C. .Iurbination is continued for 15 minutes at thistemperature. Subsequently, the reaction solution is cooled and thenshaken with 100 cc. of ether and 100 cc. of -1 N-hydl'ochloric acid.After separation of thelayers, the aqueous acid part is renderedalkaline by means'ot caustic soda and the precipitating oil is taken upin ether. The ether is evaporated after drying and the residue distilledunder high vacuum. The Q-(B-dimethylaminoethyl-mercaptoacetyD-aminobenzothiazole distills under 0.01 mm. at'l97-205 C. By carefullytreating a methanolic solution of the novel benzothiazole with water,the substance is obtained in form of colourless crystals melting at 43-.44" C. 1

Example 2 "The compound described in Example 1 can also be obtained byreacting Z-mercapto-acetylamino benzothiazole '(M.P. 191 C.) withdimethylaminoethylchloride in the presence of sodium ethylate inethanol.

e Example 3 .When reacting 57 g. of 2-chloroacetamino benzothiazole with34 g. of diethylaminoethanethiol in 200 cc. of acetonitrile in a manneranalogous to that described in Example 1, 52 g. of 2-(3-diethylaminoethyl-mercaptoacetyD-zimino-benzothiazole melting atSci-87 C. are

obtained. 7 V A Example 4 The reaction of 42.3 g. of 2-amino-6-ethoxybenzothi azole with 30.8 g. of chloroacetylchloride in 300 cc. ofacetone in the presence of 44.4 g. of crystalline sodium acetate leadsto 40 g. of 2-chloroacetylamino-6-ethoxy benzothiazole, which melts atl69170 C. The compound can be purified by recrystallisation flom aceticacid.

20 g. of the above resulting chloroacetyl compound are mixed with 10.4g. of diethylaminoethanethiol in 80 cc. of acetonitrile. Immediately, aviolent reaction sets in. After the reaction has subsided, there followsturbination tor 15 minutes at 40 C. and working up in the mannerindicated in Example 1. By recrystallisation from dilute methanol, 21-22g. of 2-(fi-diethylaminoethyl-mercapto acetyl) amino-G-ethoxybenzothiazole are obtained; it melts at 137-138" C. The new compoundforms crystalline salts not only with hydrochloric acid, phosphoric acidand sulfuric acid, but with oxalic acid, fumaric acid, succinic acid,citric acid and salicylic acid as Well.

When reacting 2-chloroacetamino-6-ethoxy benzothiazole withpyrrolidinoethanethiol, the 2-(l3-pyrrolidinoethyl mercapto acetyl)amino-6-ethoxy benzothiazole melting at 141-l42 C. is obtained.

Example 5 50-55 g. of the chloroacetyl derivative are obtained from 69g. of Z-amino-G-chloro benzothiazole, 76 g. of crystalline sodiumacetate and 53.2 g. of chloroacetylchloride in 400 cc. of acetone..After recrystallisation from acetic acid, the new product melts at 212C.

10.7 g. of diethylaminoe-thanethiol are added to a solution of 20 g. ofthe above resulting chloroacetyl derivative infl60 cc. of acetonitrile.The temperature rises by itself. to about 50 C.v The whole is now heatedto boiling for 25 hours and after cooling treated with 200 cc. of ether,which causes immediately crystallisation. After some standing, thecrystals are filtered 'oif with suction, washed first with ether andthen with ethanol and subsequently dried. This yields 23.9 g. of asubstance melting -at'181.C., which represents the hydrochloride of the2- {p diethylaminoethyl mercapto-acetyl)-amino-6-chloro abenzothiazole.This hydrochloride is very readily soluble in water and fairly. wellsoluble in hot methanol and ethanol.

Instead of diethylaminoethanethiol, it is likewise possible to reactfi-piperidinoethanethiol with the chloroacetyl derivative, therebyobtaining the 2-(p-piperidinoethylmercapto-acetyl)-amino-6-chlorobenzothiazole, which boils under 0101 at 205-207 C.

Example 6 In a manner analogous to that described in Example 5, there isobtained from 7 g. of 2-chloroacetylamino-6- chloro benzothiazole and3.2 g. of dimethylaminoethanethiol in'50 cc. of acetonitrile thehydrochloride of the 2 (fi dimethylaminoethyl mercapto acetyl) amino-6-chloro benzothiazole, which melts at 143-145 C. It can berecrystallised from absolute ethanol/ absolute ether.

Example 7' 1 70 g. of 2-chloroacetylamino-6-chloro benzothiazole in 500cc. of acetonitrile are reacted in the usual manner with 53 g. ofdi-n-butyl-aminoethanethiol. The base is set free h-om the precipitatinghydrochloride with the aid of caustic soda. The base is taken up inether and the etherealsolution washed with caustic soda and water andthen dried. After distillation of the ether, the base begins tocrystallise. Upon recrystallisation from petroleumether, it melts at72-73 C. The furnarate or the maleate can be produced in etherealsolution from the resulting Z-(fi-di-n-butylaminoethyl merc'apto acetyl)amino 6- chloro benzothiazole. s V The reaction of2-chloro-acetylamino-6-chloro benzothiazole withN-n-butylaminoethanethiol leads to the benzothiazole derivative. of theformula Example 9 By reacting 30 g. of 2-chloroacetylamino-4,6-dichlorobenzothiazole with 11 g. of dimethylaminoethanethiol in 200 cc. ofacetonitrile, 32 g. of 2-(B-dimethylaminoethylmercapto-acetyl)-amino 4,6dichloro benzothiazole are obtained. The new product boils under 0.02mm. at 225-227 C.

The hitherto unknown 2amino-4,6-dichloro benzothiazole is obtained inthe following manner:

50 g. of 2,4-dichloroaniline and g. of ammoniumrhodanide are dissolvedin 285 cc. of hot methanol. 164 g. of copper chloridein 285 cc. ofmethanol are added dropwise in such manner that the solution remainscontinuously boiling. The heating is continued for 2 hours withuninterruptedstirring- Subsequently, 1000 cc. of 2: N-hydrochloric'acidare added, the copper rhodanide is filtered off withsuction'andextracted twice with ,250 cc.'each of hot water. The combinedaqueous/methanolic solutions are treated with coal and filtered. Thefiltrate is adjusted to a pH value of 8 and cooled. At the end of 24hours, the precipitating mass is filtered with suction andrecrystallised from methanol. The resulting 2-amino-4,6,-dichlorobenzothiazole melts at 253-255" C. Extraction of the copper rhodanideresidue with aqueous'methane-sulfonic acid solution yields furtherquantities of the prQducL-TIhejyield totals between 25 and 30%l f 5: if.'11 Li Q. i

Example When reacting 2-chloroacetylamino-4,6-dichloro benzothia'zolewith diethylaminoethanethiol in a manner analogous to that described inExample 1, the Z-(B-diethylaminoethyl-mercapto-acetyl) -amino 4,6dichloro benzothiazole is obtained as an oil boiling under 0.01 mm. at208-21l C. It is readily soluble in dilute mineral acids and also formscrystalline salts with such acids, namely with sulfuric acid,hydrochloric acid, and phosphoric acid. Crystalline salts which arereadily soluble in water can likewise be obtained with the aid oforganic acids, such as for instance fumaric acid, maleic acid, phthalicacid, p-hydroxy-benzoic acid, undecylenic acid and further unsaturatedparafiin-carboxylic acids.

By reacting 2-chloroacetylamino 6 methyl mercapto benzothiazole withdiethylaminoethanethiol in acetonitrile, the 2- (,B-diethylamino-ethylmercapto-acetyl) amino-6- methylmercapto benzothiazole is obtained. Thenew product boils under 0.015 mm. at 198199 C.

Example 1 When working in a manner analogous to that described inExample 1, the Z-(B-dimethylaminoethyl-mercaptwacetyl)-a.mino-4,6-dibromo benzothiazole is obtained from2-chloroacetylamino-4,6-dibromo benzothiazole anddimethylaminoethanethiol in acetonitrile. The new product, obtained asan oil, boils under 0.02 mm. at 230-235 C.

It is furthermore possible to obtain by working in a manner analogous tothat described by the examples, the following new products:

2-[a-(p-pyrrolidinoethyl-mercapto) -propionyl] -amino- 6-chlorobenzothiazole, B.P. 0.01 mm.: 210-212 C., from2-(u-bromopropionyl)-amino-6-chloro benzothiazole andB-pyrrolidinoethanethiol;

2-[a (;3- diethylaminoethyl mercapto) propionyllamino-G-methylbenzothiazole;

2-(5 diethylaminoethyl mercapto acetyl) amino-6- methyl benzothiazole;

Z-(fi-diethylaminopropyl mercapto acetyl) amino-6- methyl benzothiazole.

What I claim is:

1. New chemical compounds selected from the group consisting ofbenzothiazoles and salts thereof with nontoxic acids, saidbenzothiazoles having the formula wherein B2 is of the group consistingof the monochlorobenzothiazolyl-Z-radical, the monobromo-benzothiazolyl-Z-radical, the dichloro-benzothiazolyl-Z-radical, and thedibromo-benzothiazolyl-2-radica1, R and R represent alkylene radicalswhich contain together not more than 6 carbon atoms, and Am is of thegroup consisting of the monoalkylamino group, the dialkylamino group,the pyrrolidino group, the piperidino group and the morpholino group,whereby the monoalkylamino group and dialkylamino group do not containmore than 8 carbon atoms.

2. The new chemical compound of the formula 3. The new chemical compoundof the formula N I GzHs SJ-NHCOOH1SCHn-CH2- 6. 4. The new chemicalcompound of the formula 5. The new chemical compound of the formula 6.The new chemical compound of the formula I GzHs S NH-C O-CHr-S-CHr-CH2N7. The new chemical compound of the formula 8. The new chemical compoundof the formula 9. A process for the production of new benzothiazoles ofthe formula Bz--NHR -X with a compound of the formula wherein one of thesymbols X represents a halogeno atom and the other symbol X' representsthe thiol group.

10. A process for the production of new benzothiazoles of the formulawherein Bz is of the group consisting of themonochlorobenzothiazolyl-Z-radical, the monobromo-benzothiazolyl-2-radica1, the dichloro-benzothiazolyl-Z-radical, and thedibromo-benzothiazolyl-Z-radical, R and R represent alkylene radicalswhich contain together no more than 6 carbon atoms, and Am is of thegroup consisting of the monoalkylamino group, the dialkylamino group,the pyrrolidino group, the piperidino group, and the morpholino group,whereby the monalkyl-amino group and dialkylamino group do not containmore than 8 carbon atoms,

"."2,952Q.87 7. 8 said prdcessomprisifig'reapting hbenzbthiazoleideriva-11. A process as claimed ingelaim 10, wherein the tive of the formulasolvent is acetonitrfle K f I 7v Bz. .-NH-CO-R1halo g eno :f'j a". 1f 1;withjra compound of the formula j 5 f ".9 f' 5 V STATES'PATENTS j 1 in alower alkyl cyanide as solvent, 2,657,136 i i lKflottl e t -31. .."Oct-.27,

1. NEW CHEMICAL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OFBENZOTHIAZOLES AND SALTS THEREOF WITH NONTOXIC ACIDS, SAIDBENZOTHIAZOLES HAVING THE FORMULA